A bioinformatics driven map of pharmacogenomic variation and genetic variants in Alzheimer’s disease therapy
https://doi.org/10.14412/2074-2711-2025-6-61-68
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia globally. First-line AD therapy using cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine shows interindividual variation in effectiveness, indicating the involvement of genetic factors. This study aims to identify genetic variants that influence response to AD therapy through bioinformatics and pharmacogenomic approaches. Data were retrieved from PharmGKB and analyzed based on therapy efficacy, allele frequencies across populations (1000 Genomes), and gene expression (GTEx). Four SNP variants were found to be relevant: rs6494223 (CHRNA7), rs3793790 and rs2177370 (CHAT), and rs1803274 (BCHE). Specific genotypes such as CC (rs6494223), GG and AA (CHAT), and TT (rs1803274) showed better therapy response. Expression analysis showed that the CHAT gene is highly expressed in the brain, reinforcing its pharmacogenetic relevance. In contrast, CHRNA7 and BCHE showed high expression in non-neuronal tissues, yet still play a systemic role in acetylcholine metabolism. Variations in allele frequencies between populations were also identified, underscoring the importance of population-based therapeutic approaches. These results support the importance of simple genetic screening in the development of precision therapies for Alzheimer’s. This study demonstrates that integrating pharmacogenomic and gene expression data can provide a better understanding of the heterogeneity of AD therapy response and open the possibility of personalized treatment based on the patient’s genetic profile.
Supporting agencies: The investigation has not been sponsored
About the Authors
D. P. Amukti
Alma Ata University
Indonesia
Competing Interests:
Indonesia
Danang Prasetyaning Amukti - Department of Pharmacy, Faculty of Medicine and Health Science.
Jl. Brawijaya No.99, Tamantirto, Kasihan, Bantul, Yogyakarta, 55183
Competing Interests:
There are no conflicts of interest
N. Kusumawardani
Alma Ata University
Indonesia
Competing Interests:
Indonesia
Jl. Brawijaya No.99, Tamantirto, Kasihan, Bantul, Yogyakarta, 55183
Competing Interests:
There are no conflicts of interest
D. Estiningsih
Alma Ata University
Indonesia
Competing Interests:
Indonesia
Jl. Brawijaya No.99, Tamantirto, Kasihan, Bantul, Yogyakarta, 55183
Competing Interests:
There are no conflicts of interest
T. Herlina
Alma Ata University
Indonesia
Competing Interests:
Indonesia
Jl. Brawijaya No.99, Tamantirto, Kasihan, Bantul, Yogyakarta, 55183
Competing Interests:
There are no conflicts of interest
E. Nurinda
Alma Ata University
Indonesia
Competing Interests:
Indonesia
Jl. Brawijaya No.99, Tamantirto, Kasihan, Bantul, Yogyakarta, 55183
Competing Interests:
There are no conflicts of interest
R. Indah Pratami
Ahmad Dahlan University
Indonesia
Competing Interests:
Indonesia
Faculty of Pharmacy.
Jl. Kapas 9, Semaki, Umbulharjo, Yogyakarta 55166
Competing Interests:
There are no conflicts of interest
References
1. Stotani S, Giordanetto F, Medda F. DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem. 2016 Apr;8(6):681-96. doi: 10.4155/fmc-2016-0013
2. Engin AB, Engin A. Alzheimer’s Disease and Protein Kinases. Adv Exp Med Biol. 2021;1275:285-321. doi: 10.1007/978-3-030-49844-3_11
3. Chinnathambi S, Kumarappan M, Chandrashekar M. The cross-talk between ApoE and Tau protein in Alzheimer’s disease. Adv Protein Chem Struct Biol. 2025;146:201-19. doi: 10.1016/bs.apcsb.2024.08.004
4. Ahmed S, Khan ST, Zargaham MK, et al. Potential therapeutic natural products against Alzheimer’s disease with Reference of Acetylcholinesterase. Biomed Pharmacother. 2021 Jul;139:111609. doi: 10.1016/j.biopha.2021.111609
5. Sharma P, Tripathi MK, Shrivastava SK. Cholinesterase as a Target for Drug Development in Alzheimer’s Disease. Methods Mol Biol. 2020;2089:257-86. doi: 10.1007/9781-0716-0163-1_18
6. Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018 Jul 1;141(7):1917-33. doi: 10.1093/brain/awy132
7. Amukti DP, Wazni AR, Irham LM, et al. Identifying pathogenic variants associated with Alzeimer by integrating genomic databases and bioinformatics approaches. InE3S Web of Conferences. 2024. Vol. 501. P. 01021. EDP Sciences.
8. Russo P, Kisialiou A, Moroni R, et al. Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer’s Disease. Curr Drug Targets. 2017;18(10):1179-90. doi: 10.2174/1389450116666151001111826
9. Guo M, Wang ZJ, Yang HW, et al. Influence of Genetic Polymorphisms on Mycophenolic Acid Pharmacokinetics and Patient Outcomes in Renal Transplantation. Curr Drug Metab. 2018;19(14):1199-205. doi: 10.2174/1389200219666171227201608
10. Jamal R, Shaikh MA, Taleuzzaman M, et al. Key biomarkers in Alzheimer’s disease: Insights for diagnosis and treatment strategies. J Alzheimers Dis. 2025 Jun;105(3):679-96. doi: 10.1177/13872877251330500
11. Budiawan P, Prasetyaning A, Muhammad I, et al. Pharmacogenomics for treatment response in patients with Stevens-Johnson syndrome: An updated review. Scr Med (Brno). 2025;56(3):579-87.
12. Gustinanda R, Irham LM, Supadmi W, et al. Gene variants that may cause adverse drug reactions in non-Hodgkin’s lymphoma therapy: a genomic and bioinformatics approach. Siberian Journal of Oncology. 2025;24(3):50-64 (In Russ.). doi: 10.21294/1814-4861-2025-243-50-64
13. Amukti DP, Irham LM, Surono S, et al. Genomic variants and epidemiology of atherosclerosis Р worldwide correlation analysis and utilization of atherosclerosis gene variants for identification of drug target candidates with bioinformatics approach. Bulgarian Cardiology. 2024 Dec 31;30(4):108-20. Available at: https://journal.bgcardio.org/article/145391/
14. Gumelar G, Ulfa MM, Amukti DP, et al. Harnessing Genomic and Bioinformatic Data to Broaden Understanding of Leukaemia Across Continents. Scripta Medica (Banja Luka). 2024 Nov 1;55(6):717-25.
15. Cacabelos R. Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer’s disease. Expert Opin Drug Metab Toxicol. 2020 Aug;16(8):673701. doi: 10.1080/17425255.2020.1779700
16. Russo P, Kisialiou A, Moroni R, et al. Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer’s Disease. Curr Drug Targets. 2017;18(10):1179-90. doi: 10.2174/1389450116666151001111826
17. Sokolow S, Li X, Chen L, et al. Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment. J Alzheimers Dis. 2017;56(1):229-37. doi: 10.3233/JAD-160562
18. Yadav R, Deepshikha D, Srivastava P. Homology Modeling and Protein Interaction Map of CHRNA7 Neurogenesis Protein. Ann Neurosci. 2017 Jul;24(3):173-9. doi: 10.1159/000477155
19. Chou PS, Huang LC, Hour TC, et al. Impact of the CYP2D6 single nucleotide polymorphism on the concentration of and therapeutic response to donepezil in mild-to-moderate Alzheimer’s disease. J Formos Med Assoc. 2022 Jan;121(1 Pt 2):409-15. doi: 10.1016/j.jfma.2021.05.026
20. Zhu B, Chen C, Moyzis RK, et al. The Choline Acetyltransferase (CHAT) Gene is Associated with Parahippocampal and Hippocampal Structure and Short-term Memory Span. Neuroscience. 2018 Jan 15;369:261-8. doi: 10.1016/j.neuroscience.2017.11.021
21. Zhong G, Guo J, Pang C, et al. Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer’s disease: Design, synthesis, and biological evaluation. Bioorg Chem. 2023 Jan;130:106224. doi: 10.1016/j.bioorg.2022.106224
22. Rocha-Dias PF, Simao-Silva DP, Silva SSLD, et al. Influence of a genetic variant of CHAT gene over the profile of plasma soluble ChAT in Alzheimer disease. Genet Mol Biol. 2020 Nov 20;43(4):e20190404. doi: 10.1590/1678-4685GMB-2019-0404
23. Jasiecki J, Wasаg B. Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer’s Disease-Could BCHE Genotyping Be Helpful in Alzheimer’s Therapy? Biomolecules. 2019 Oct 9;9(10):592. doi: 10.3390/biom9100592
24. Zuniga Santamaria T, Yescas Gomez P, Fricke Galindo I, et al. Pharmacogenetic studies in Alzheimer disease. Neurologia (Engl Ed). 2022 May;37(4):287-303. doi: 10.1016/j.nrl.2018.03.025
25. Ford GR, Niehaus A, Joubert F, Pepper MS. Pharmacogenetics of CYP2A6, CYP2B6, and UGT2B7 in the Context of HIV Treatments in African Populations. J Pers Med. 2022 Dec 5;12(12):2013. doi: 10.3390/jpm12122013
26. Bharti N, Banerjee R, Achalare A, et al. Estimation of genetic variation in vitiligo associated genes: Population genomics perspective. BMC Genom Data. 2024 Jul 26;25(1):72. doi: 10.1186/s12863-024-01254-6
27. Sangadi DK, Sangadi A, Placeres-Uray F, et al. Enhancing cognitive function in chronic TBI: The Role of α7 nicotinic acetylcholine receptor modulation. Exp Neurol. 2024 Feb;372:114647. doi: 10.1016/j.expneurol.2023.114647
28. Ramos FM, Delgado-Velez M, Ortiz AL, et al. Expression of CHRFAM7A and CHRNA7 in neuronal cells and postmortem brain of HIV-infected patients: considerations for HIV-associated neurocognitive disorder. J Neurovirol. 2016 Jun;22(3):327-35. doi: 10.1007/s13365-015-0401-8
29. Gamage R, Zaborszky L, Münch G, Gyengesi E. Evaluation of eGFP expression in the ChAT-eGFP transgenic mouse brain. BMC Neurosci. 2023 Jan 17;24(1):4. doi: 10.1186/s12868-023-00773-9
30. Szwajgier D, Baranowska-Wojcik E, Winiarska-Mieczan A, Gajowniczek-Alasa D. Honeys as Possible Sources of Cholinesterase Inhibitors. Nutrients. 2022 Jul 20;14(14):2969. doi: 10.3390/nu14142969
31. Szigeti K, Ihnatovych I, Birkaya B, et al. CHRFAM7A: A human specific fusion gene, accounts for the translational gap for cholinergic strategies in Alzheimer’s disease. EBioMedicine. 2020 Sep;59:102892. doi: 10.1016/j.ebiom.2020.102892
32. Kunii Y, Zhang W, Xu Q, et al. CHRNA7 and CHRFAM7A mRNAs: co-localized and their expression levels altered in the postmortem dorsolateral prefrontal cortex in major psychiatric disorders. Am J Psychiatry. 2015 Nov 1;172(11):1122-30. doi: 10.1176/appi.ajp.2015.14080978
33. Cacabelos R. Pharmacogenetic considerations when prescribing cholinesterase inhibitors for the treatment of Alzheimer’s disease. Expert Opin Drug Metab Toxicol. 2020 Aug;16(8):673-701. doi: 10.1080/17425255.2020.1779700
34. Suzuki M, Wang T, Garretto D, et al. Disproportionate Vitamin A Deficiency in Women of Specific Ethnicities Linked to Differences in Allele Frequencies of Vitamin A-Related Polymorphisms. Nutrients. 2021 May 21;13(6):1743. doi: 10.3390/nu13061743
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For citations:
Amukti DP, Kusumawardani N, Estiningsih D, Herlina T, Nurinda E, Indah Pratami R. A bioinformatics driven map of pharmacogenomic variation and genetic variants in Alzheimer’s disease therapy. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2025;17(6):61-68. https://doi.org/10.14412/2074-2711-2025-6-61-68
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